PROJECT SUMMARY Optimal brain health requires effective cerebrovascular function, adequate perfusion, and highly responsive blood flow regulation. If any of these, or a combination of these, are compromised, there are implications for brain health. Previous research demonstrated that cerebral hypoperfusion and inadequate cerebrovascular responses to vasoactive stimuli may precede the onset of cognitive impairment. Indeed, adults with cognitive impairment, including vascular dementia and Alzheimer?s disease, exhibit inadequate cerebral perfusion. Yet, the majority of evidence linking hypoperfusion to cognition comes from preclinical models, and there is minimal research on how chronic cerebral hypoperfusion may impact cerebrovascular control in humans. Accordingly, there is a critical need for more research on the pathophysiology of cognitive decline in humans. Our preliminary data indicate that adults with cerebral anatomical variations demonstrate cerebral hypoperfusion and reduced cerebrovascular reactivity. This finding is important as it presents our investigative team with a group of individuals with a cerebral anatomical variant that may naturally model a state of chronic cerebral hypoperfusion. Our overarching hypothesis is that chronic hypoperfusion, resulting from a specific variation in cerebrovascular architecture, impacts cerebral blood flow regulation which increases the risk of cognitive impairment. Thus, the objectives of this application are to investigate chronic models of hypoperfusion in humans, examine compensatory mechanisms to maintain perfusion, and determine the potential impact on cognitive health. For each aim, we will recruit participants from a unique, risk-enriched cohort of middle-aged and older adults from the University of Wisconsin-Madison Alzheimer?s Disease Research Center. This cohort has extensive longitudinal data on medical health, genetics, and cognitive biomarkers. We will use state-of-the-art imaging modalities to identify differences in cerebrovascular architecture and quantify cerebral blood flow regulation in the following specific aims: In Specific Aim 1, we will examine the compensatory responses to a model of acute hypoperfusion and determine the impact of chronic cerebral hypoperfusion observed in adults with specific cerebral anatomical variations. In Specific Aim 2, we will utilize aerobic exercise to characterize the cerebrovascular responses to acute hyperperfusion and determine the impact of cerebral anatomical variations. In Specific Aim 3 we will determine the impact of cerebral anatomical variations on cerebrovascular control and establish whether adults with cerebral anatomical variations are at a higher risk of cognitive decline. This project will be the first systematic investigation of cerebrovascular control mechanisms in acute and chronic cerebral hypoperfusion in humans, and will address the potential implications of long-term hypoperfusion for cognitive health. Upon completion, we will understand the impact of cerebral anatomical variations on cerebrovascular health and the risk of Alzheimer?s disease and related dementias.